Manufacturing process

ABSTRACT

A method for the manufacture of clevidipine by reaction of an inorganic salt of 4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine-carboxylate and chloro methyl butyrate.

This application is a 371 of PCT/SE99/02155 filed Nov. 22, 1999.

FIELD OF THE INVENTION

The present invention relates to an improved method for the manufactureof clevidipine (butyroxymethyl methyl4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate)via the route of reacting4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylicacid with chloromethyl butyrate.

PRIOR ART

WO 95/12578 discloses a method for the preparation of clevidipine usingas reactants4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylicacid. The disclosed method has several drawbacks.

DISCLOSURE OF THE INVENTION

It has now been found that clevidipine, which is a short-actingcalcium-channel blocker, can be prepared in a manner that is faster,reduces the amount of byproducts, is more environmentally sound andgives a better yield than the process disclosed in WO 95/12578. It alsoincreases the stability of one of the intermediates allowing it to beisolated and stored without drying.

The method according to the invention uses an inorganic salt instead ofthe neutral form of carboxylic acid.

The method which is schematically outlined below is characterized byreaction of compound A, wherein A⁺ is a positively charged inorganic ionwith chloromethyl butyrate to obtain clevidipine.

Compound A is reacted with chloromethyl butyrate optionally in thepresence of a corresponding hydrogen carbonate (preferable KHCO₃) inrefluxing acetonitrile. A⁺ is preferably potassium or sodium, mostpreferably potassium. Preferably the inorganic salts are removed byfiltration and the product is crystallized. The crystallization can beperformed for instance by the addition of isopropanol and water withsubsequent cooling. It can also be crystallized by exchanging solventfrom acetonitrile to a mixture of alcohol, such as ethanol orisopropanol, preferably ethanol, and water with repeated evaporations.In the further purification of the product the crystals are washed witha mixture of water and ethanol or isopropanol. The product can bedissolved in refluxing isopropanol, crystallized by cooling, isolated byfiltration and finally washed with a water and isopropanol mixture.

In a preferred embodiment Compound A is reacted with chloromethylbutyrate (1.2-2.8 eq., preferably 1.4-1.6 eq.). The reactants arecharged together with potassium hydrogen carbonate (1.5-0.4 eq.,preferable 0.8-0.6 eq.) and the solvent acetonitrile (3-12 ml/g ofCompound A).

Preparation of Compound A starting material

Cyanoethyl methyl4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylateis reacted with potassium hydroxide or other suitable hydroxide e.g.sodium hydroxide in isopropanol over night at room temperature. Some ofthe solvent can be evaporated off to increase the yield or the productis isolated direct without any evaporation and washed with isopropanol.

WORKING EXAMPLES Example 1

Potassium4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate(10.6 kg 27 mol; 1 eq), acetonitrile (63 L) and chloromethyl butyrate(5.8 kg ,42 mol; 1.6 eq) were heated to reflux. After 3.5 h at refluxthe inorganic salts were filtered off and washed with warm acetonitrile(25 L). The temperature of the solution was adjusted to 50° C. and then2-propanol (17 kg) and water (110 kg) were added to the solution. Theslurry was left over night (8.5 h) at 25° C. before the product wasisolated and washed with a mixture of 2-propanol (16 kg) and water (28kg). This gave clevidipine-crude (11.0 kg, 90%) as a white to slightlyyellowish solid. LC-purity 99.58%, LC-assay 98.93% (w/w)

Example 2

Potassium4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate(6.7 g, 15 mmol; 1 eq), KHCO₃ (0.9 g, 9 mmol; 0.6 eq), acetonitrile (50ml) and chloromethyl butyrate (2.7 ml, 21 mmol; 1.4 eq) were heated toreflux. After 4.5 h at reflux the inorganic salts were filtered off andwashed with warm acetonitrile (20 ml). The solvent was exchanged fromacetonitrile to ethanol:water (˜35 ml, 2:1). The solution was left overnight (17 h) at ambient temperature before the product was isolated andwashed with a mixture of ethanol:water (3*5 g, 3:1). This gaveclevidipine-crude (5.2 g, 76%) as a white to slightly yellowish solid.LC-purity 99.2%

Example 3

Sodium4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate(7.0 g, 15 mmol; 1 eq), NaHCO₃ (0.8 g, 9 mmol; 0.6 eq), acetonitrile (50ml) and chloromethyl butyrate (2.7 ml , 21 mmol; 1.4 eq) were heated toreflux. After 5 h at reflux the inorganic salts were filtered off andwashed with warm acetonitrile (20 ml). The solvent was exchanged fromacetonitrile to ethanol:water (˜35 ml, 2:1). The solution was left overnight (17 h) at ambient temperature before the product was isolated andwashed with a mixture of ethanol:water (3*5 g, 3:1). This gaveclevidipine-crude (5.1 g, 74%) as a white to slightly yellowish solid.LC-purity 98.8%

Example 4

Clevidipine crude (7.5 g, 16 mmol) and 2-propanol (38 g) were heated toreflux. The temperature was adjusted to 40° C. and water (48 g) wasadded. The solution was left over night at ambient temperature beforethe product was isolated and washed with a mixture of 2-propanol:water(2*10 g (45:55% w/w)). This gave clevidipine (7.2 g, 96%) as a white toslightly off white solid. LC-purity 99.9%

What is claimed is:
 1. An improved method for the manufacture ofclevidipine, comprising mixing a compound of the formula I,

wherein A⁺ is an inorganic cation such that the compound is in saltform, with a solvent to form a mixture substantially free of the freeacid of the compound, and reacting the compound of formula I withchloromethyl butyrate.
 2. The method according to claim 1, wherein thereaction is performed in the presence of A⁺HCO₃, wherein A⁺ is aninorganic cation.
 3. The method according to claim 1, wherein thereaction is performed in acetonitrile.
 4. The method according to claim3, wherein the reaction is performed in refluxing acetonitrile.
 5. Themethod according to claim 1, wherein A⁺ is a potassium or sodium ion. 6.The method according to claim 1, wherein A⁺ is a potassium ion.
 7. Themethod according to claim 2, wherein A⁺ is a potassium ion and thecorresponding hydrogen carbonate is potassium hydrogen carbonate.
 8. Themethod according to claim 1, wherein the obtained clevidipine ispurified by crystallization.
 9. The method according to claim 8, whereinthe obtained clevidipine is crystallized by the addition of isopropanoland water with subsequent cooling.
 10. The method according to claim 1,wherein the molar ratio between the compound of formula I andchloromethyl butyrate in the initial reaction mixture is 1:1.2-2.8. 11.A method for the manufacture of clevidipine in the form of apharmaceutical preparation wherein clevidipine is produced according toany of the preceding claims and thereafter purified clevidipine isadmixed with an excipient, diluent or carrier to provide thepharmaceutical preparation.
 12. The method of claim 1, wherein theclevidipine produced is substantially free of the free acid of thecompound.